Immunization with a mimotope of GD2 ganglioside induces CD8+ T cells that recognize cell adhesion molecules on tumor cells.
The GD2 ganglioside expressed on neuroectodermal tumor cells has been used as a target for passive and active immunotherapy in patients with malignant melanoma and neuroblastoma. We have reported that immunization of mice with a 47-LDA mimotope of GD2, isolated from a phage display peptide library with anti-GD2 mAb 14G2a, induces MHC class I-restricted CD8(+) T cell responses to syngeneic neuroblastoma tumor cells. The cytotoxic activity of the vaccine-induced CTLs was independent of GD2 expression, suggesting recognition of a novel tumor-associated Ag cross-reacting with 47-LDA. Glycan microarray and immunoblotting studies using 14G2a mAb demonstrated that this Ab is highly specific for the entire carbohydrate motif of GD2 but also cross-reacts with a 105 kDa glycoprotein expressed by GD2(+) and GD2(-) neuroblastoma and melanoma cells. Functional studies of tumor cells grown in three-dimensional collagen cultures with 14G2a mAb showed decreases in matrix metalloproteinase-2 activation, a process regulated by the 105 kDa-activated leukocyte cell adhesion molecule (ALCAM/CD166). A recombinant CD166 glycoprotein was shown to be recognized by 14G2a Ab and inhibition of CD166 expression by RNA interference ablated the cell sensitivity to lysis by 47-LDA-induced CD8(+) T cells in vitro and in vivo. The binding of 14G2a to CD166 was not disruptable by a variety of exo- and endo-glycosidases, implying recognition of a non-glycan epitope on CD166. These results suggest that the vaccine-induced CTLs recognize a 47-LDA cross-reactive epitope expressed by CD166, and reveal a novel mechanism of induction of potent tumor-specific cellular responses by mimotopes of tumor-associated carbohydrate Ags.
Wierzbicki
Andrzej
A
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Gil
Margaret
M
Ciesielski
Michael
M
Fenstermaker
Robert A
RA
Kaneko
Yutaro
Y
Rokita
Hanna
H
Lau
Joseph T
JT
Kozbor
Danuta
D
D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000276:immunology / Q000378:metabolism; D018303:Ganglioglioma / Q000276:immunology / Q000378:metabolism; D005732:Gangliosides / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008805:Mice, Inbred A; D018716:Molecular Mimicry / Q000276:immunology; D009447:Neuroblastoma / Q000276:immunology* / Q000378:metabolism
D020410:Activated-Leukocyte Cell Adhesion Molecule; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D005732:Gangliosides; C019403:ganglioside, GD2